Annals for Hospitalists Inpatient Notes - Venous Thromboembolism Prophylaxis in COVID-19: Making Sense of the Evidence
Authors: Christopher A. Smith, Geoffrey D. Barnes
Journal: Annals of Internal Medicine (2022)

Web ExclusivesJune 2022Annals for Hospitalists Inpatient Notes - Venous Thromboembolism Prophylaxis in COVID-19: Making Sense of the EvidenceFREEChristopher A. Smith, MD and Geoffrey D. Barnes, MD, MScChristopher A. Smith, MDDivision of Hospital Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (C.A.S.)Search for more papers by this author and Geoffrey D. Barnes, MD, MScDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (G.D.B.).Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M22-1425 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail In patients hospitalized with COVID-19, venous thromboembolism (VTE) has been recognized as an important complication despite the use of prophylactic anticoagulation. The causes of this hypercoagulability in COVID-19 include a hyperinflammatory state, endothelial injury, platelet and complement activation, and coagulopathy.Early in the pandemic, clinicians began exploring the potential benefits of nonstandard or therapeutic-intensity anticoagulation for patients hospitalized with COVID-19. Heparin products were of particular interest because of their antithrombotic effect as well as anti-inflammatory and potential antiviral properties. Several trials have now evaluated whether therapeutic-intensity anticoagulation safely reduces thrombosis in these patients. Leading organizations, including the National Institutes of Health, American College of Chest Physicians, American Society of Hematology, and Anticoagulation Forum, have also released guidelines and guidance statements about this topic.Prevention of VTE in Patients Hospitalized With COVID-19: Evaluating the EvidenceTrials have evaluated various anticoagulant agents and doses in patients with COVID-19 not requiring supplemental oxygen (asymptomatic or mildly ill), patients requiring nonintensive care (moderately ill), and patients requiring intensive care unit (ICU)–level care (critically ill).The multiplatform trials (1) (ATTACC [Antithrombotic Therapy to Ameliorate Complications of COVID-19], ACTIV-4a [Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE], and REMAP-CAP [Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia]) were large international studies comparing nontherapeutic (standard or intermediate intensity) thromboprophylaxis to therapeutic-intensity unfractionated heparin or low-molecular-weight heparin (LMWH) for up to 14 days, until discharge, or until hypoxia resolution in hospitalized patients. In moderately ill patients, therapeutic-intensity dosing increased the probability of hospital discharge with reduced need for organ support (high-flow oxygen, ventilatory support, or vasopressor support) (adjusted odds ratio [aOR], 1.27 [95% CI, 1.03 to 1.58]). D-dimer levels at enrollment did not influence outcomes, however, and survival to discharge was not significantly different between the therapeutic and nontherapeutic groups.Additional studies in moderately ill patients with COVID-19 with elevated D-dimer levels (RAPID [Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic] and HEP-COVID [Systemic Anticoagulation With Full Dose Low Molecular Weight Heparin (LMWH) Vs. Prophylactic or Intermediate Dose LMWH in High Risk COVID-19 Patients] trials) found reduced arterial and venous thromboembolism and all-cause mortality in patients assigned to therapeutic-intensity unfractionated heparin or LMWH compared with prophylactic or intermediate-intensity heparin (2, 3). In contrast, the ACTION (Randomized Clinical Trial to Evaluate a Routine Full Anticoagulation Strategy in Patients With Coronavirus [COVID-19]) trial, which compared therapeutic-intensity rivaroxaban with prophylactic-dose heparin, failed to show superior efficacy while noting increased major bleeding in the rivaroxaban group (4).Surprisingly, when the multiplatform trials studied critically ill patients with COVID-19 requiring ICU-level care at the time of randomization, therapeutic-intensity anticoagulation did not result in clinical benefit (or even a trend toward benefit) in terms of organ support-free days (aOR, 0.83 [CI, 0.67 to 1.03]) or survival to hospital discharge (aOR, 0.84 [CI, 0.64 to 1.11]). Major bleeding was also nonsignificantly increased with therapeutic-intensity anticoagulation (aOR, 1.48 [CI, 0.75 to 3.04]) (5).Collectively, these data suggest therapeutic-intensity heparin improves clinical outcomes in patients hospitalized with COVID-19 who do not require ICU-level care early in their hospitalization and are at lower risk for bleeding. Moderately ill patients with elevated D-dimer levels may benefit more than patients with normal levels. Conversely, patients requiring ICU-level care early in their hospital course do not benefit from therapeutic-intensity heparin when compared with standard VTE prophylaxis and may have more major bleeding events.Making Sense of Conflicting Outcomes Between Moderately Ill and Critically Ill Patients With COVID-19The reasons for differing outcomes in these groups are uncertain. Patients with COVID-19 who progress to organ failure may have advanced thrombosis that becomes irreversible. Thrombotic mechanisms, such as complement and platelet activation and cytokine release, may overwhelm any benefit antithrombin inhibition provides. Also, in critically ill patients with severe pulmonary inflammation and acute respiratory distress syndrome, therapeutic-intensity anticoagulation may lead to detrimental alveolar hemorrhage.The design of the multiplatform trials may have also led to this discrepancy. Most critically ill patients were recruited in the United Kingdom (REMAP-CAP trial) where national guidelines for VTE prophylaxis in ICU-level patients recommended intermediate-intensity anticoagulation during the trial. Many moderately ill patients came from the ACTIV-4a and ATTACC trials in the United States and Brazil where intermediate-intensity heparin was less common in the standard-dose group (26.5% vs. 51.7%). This may have diluted any benefit seen from therapeutic-intensity anticoagulation in critically ill patients, although data showing benefit with intermediate-intensity versus prophylactic-dose anticoagulation is lacking. Finally, these trials recruited patients over a period when important changes in management recommendations and drug availability occurred (that is, systemic steroids, hydroxychloroquine, remdesivir, and so forth), which may have skewed outcomes based on where and when patients enrolled.Suggestions for Choosing a VTE Prophylaxis Strategy in Patients Hospitalized With COVID-19Hospitalists can draw several conclusions when considering how best to prevent VTE in patients hospitalized with COVID-19. First, patients with asymptomatic or mild COVID-19 who are hospitalized for other reasons (for example, surgery) should receive standard-dose VTE prophylaxis. Second, unfractionated heparin or LMWH should be used preferentially over alternative anticoagulants (including direct oral anticoagulants) for inpatient thromboprophylaxis. Third, “intermediate”-intensity thromboprophylaxis should only be used in the setting of a clinical trial. Fourth, therapeutic-intensity heparin (preferably LMWH) should be considered in moderately ill patients. This dose should be continued for up to 14 days or until discharge or resolution of hypoxia, whichever comes first. Hospitalists should use shared decision making with patients and consider contraindications to therapeutic-intensity anticoagulation as well as overall bleeding risk. Patients with elevated bleeding risk may warrant standard-dose VTE prophylaxis. Fifth, if moderately-ill patients receiving therapeutic-intensity VTE prophylaxis progress to critical illness, there is uncertainty about continuing the same intensity of anticoagulation versus transitioning to standard-dose VTE prophylaxis. The clinical scenario and bleeding risk should be considered when choosing anticoagulation intensity for VTE prophylaxis during intrahospital care transitions. Sixth, critically ill patients with COVID-19 requiring high-flow oxygen, ventilatory support, or vasopressors should receive standard-dose VTE prophylaxis rather than therapeutic or intermediate-intensity anticoagulation unless another indication for anticoagulation exists. Finally, patients with COVID-19 discharged from the hospital with increased risk for postdischarge thromboembolism (for example, IMPROVE VTE [International Medical Prevention Registry on Venous Thromboembolism] score ≥4) but at low risk for bleeding can be considered for extended-duration VTE prophylaxis with 10 mg of rivaroxaban daily for 35 days.Recommendations about anticoagulation intensity in COVID-19 are subject to change, as the pendulum of care has already swung several times. Data on agents targeting platelet function will also need future consideration. Finally, and most importantly, the ultimate antithrombotic weapon of choice for COVID-19 remains vaccination.References1. Lawler PR, Goligher EC, Berger JS, et al; ATTACC Investigators. Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19. N Engl J Med. 2021;385:790-802. [PMID: 34351721] doi:10.1056/NEJMoa2105911 CrossrefMedlineGoogle Scholar2. Sholzberg M, Tang GH, Rahhal H, et al; RAPID Trial Investigators. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with Covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. [PMID: 34649864] doi:10.1136/bmj.n2400 CrossrefMedlineGoogle Scholar3. Spyropoulos AC, Goldin M, Giannis D, et al; HEP-COVID Investigators. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181:1612-1620. [PMID: 34617959] doi:10.1001/jamainternmed.2021.6203 CrossrefMedlineGoogle Scholar4. Lopes RD, de Barros E Silva PGM, Furtado RHM, et al; ACTION Coalition COVID-19 Brazil IV Investigators. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397:2253-2263. [PMID: 34097856] doi:10.1016/S0140-6736(21)01203-4 CrossrefMedlineGoogle Scholar5. Goligher EC, Bradbury CA, McVerry BJ, et al; REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med. 2021;385:777-789. [PMID: 34351722] doi:10.1056/NEJMoa2103417 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Division of Hospital Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (C.A.S.)Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan (G.D.B.).Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1425.Corresponding Author: Christopher A. Smith, MD, Division of Hospital Medicine, Department of Internal Medicine, University of Michigan, F4323 UH South Unit 4, 1500 East Medical Center Drive, SPC 5220, Ann Arbor, MI 48109; e-mail, [email protected]umich.edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAnnals for Hospitalists - June 2022 Megan Mack , Matthew Luzum , and David H. Wesorick Metrics Cited byEvaluation of a fast‐and‐frugal clinical decision algorithm (‘pathways’) on clinical outcomes in hospitalised patients with COVID‐19 treated with anticoagulants June 2022Volume 175, Issue 6Page: HO2-HO3KeywordsCOVID-19HeparinHospital medicineHospitalizationsLow molecular weight heparinProphylaxisThrombosis ePublished: 21 June 2022 Issue Published: June 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...